Orthostatic intolerance (OI) is the most frequently encountered dysautonomia and the cause of much disability. As many as 500,000 Americans, most of them young women, are affected by it. Yet it is one of the least studied clinical syndromes. There is no established therapy. Its etiology is poorly understood, but is heterogeneous. In this project, we concentrate on identifying mechanisms underlying OI. We developed evidence implicating two mechanisms, a partial dysautonomia referred to as neuropathic postural tachycardia syndrome and a novel genetic disorder due to a functionally significant mutation in the norepinephrine transporter (SLC6A2) which we refer to as norepinephrine transporter (NET) deficiency. This gene is the cocaine- and antidepressant-sensitive "uptake 1" transporter which is crucial for clearing norepinephrine from the synaptic cleft. These two etiologies can explain a range of heretofore inexplicable abnormalities in cardiovascular regulation found in some patients. Our study of NET deficiency patients has led us to unexpected evidence implicating dopaminergic mechanisms in the pathophysiology of the disorder and perhaps also the orthostatic hypertension of tricyclic antidepressant use. Yet it is clear that a large portion of OI patients have different mechanisms underlying their symptoms. We have found major perturbations in volume regulation and dynamics in a subset of these patients, some of whom have as much as a 26% reduction in plasma volume when they stand for 30 minutes. The sources of interindividual differences in such dynamic volume shifts remain unknown. We propose to elucidate the systemic pathophysiology of human NET deficiency, by assessing autonomic cardiovascular regulation in mouse and human models of NET deficiency and to test specifically tailored pharmacologic interventions to determine if they will correct the pathophysiologic perturbations in OI and in the orthostatic hypeotension of NET-blocking antidepressants.